N-methyl quaternary derivatives of morphinan alkaloids such as naltrexone ((5α)-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-one sometimes referred to as N-cyclopropylmethyl-noroxymorphone) and naloxone ((5α)-4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one sometimes referred to as N-allyl-noroxymorphone) have useful pharmacological properties as potent antagonists of the mu receptor. They bind to peripheral receptors primarily located in the gastrointestinal tract, act as antagonists and effectively mitigate some of the undesirable side effects of opiate therapy such as constipation and nausea. Because of their ionic charge, however, they do not traverse the blood brain barrier into the central nervous system; hence, the central activity of opiates responsible for pain relief is not blocked in the presence of these quaternary derivatives.
In U.S. Pat. No. 4,176,186, Goldberg et al. generally describe the preparation of quaternary derivatives of certain morphinan alkaloids by quaternizing a tertiary N-substituted morphinan alkaloid with a methylating agent such as methyl bromide, methyl iodide or dimethyl sulfate. Goldberg et al. disclose that the methylating agent itself may be used as the solvent or, alternatively, another solvent medium such as methanol, ethanol, or other alcohols, methylene chloride, chloroform tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, acetonitrile, nitromethane or hexamethylphosphoric triamide may be used. Goldberg et al. state that they especially prefer acetone because the product precipitates in pure crystalline form during the reaction, and in their Example 5, they dissolve N-cyclopropylmethylnoroxymorphone in a mixture consisting of 50 mL of absolute acetone and 0.5 mL of dimethylformamide and then admix the resulting solution with methyl bromide. Methyl bromide was used in excess, greater than six-fold molar excess relative to the free base, over a period of 3 weeks in a pressure vessel.
In WO 2004/043964, Cantrell et al. disclose a process for the synthesis of naltrexone methobromide. For example, 100 g of naltrexone base was reacted with methyl bromide (MeBr) in 1-methylpyrrolidinone (NMP) at 61 to 65° C. to provide 85 g of a crude naltrexone methobromide in approximately 60 mol. % yield of approximately 90% pure naltrexone methobromide (see Example 1). Purification of the crude product was carried out in three steps to give pure naltrexone methobromide; in addition, 20% of unreacted naltrexone was disposed of in the waste streams, a significant loss. While this process constitutes significant progress in the synthesis of naltrexone methobromide and other quaternary morphinan alkaloids, a need remains for yet further improvement.
In WO 2006/127899, Doshan et al. disclose a stereoselective synthesis of the R-isomer of naltrexone methobromide by quaternization of a 3-O-protected-naltrexone with a methylating agent followed by removal of the protecting group. N-methylation of tertiary morphinan alkaloids has been shown in a previously published NMR study to be highly stereoselective yielding the R-isomer; (see Funke and de Graaf, J. Chem. Soc., Perkins Trans. II, 1985, 385). In the synthesis disclosed by Doshan et al (Example 2), 3-O-isobutyryl-naltrexone was reacted with a 4-fold excess of methyl iodide in a sealed glass pressure vessel in a nitrogen atmosphere at 88 to 90° C. for 17 hrs. The vessel was then cooled to ambient temperature and evacuated to remove unreacted methyl iodide. The product, 3-O-isobutyryl-methylnaltrexone iodide, a white solid, was dissolved in a minimum volume of dichloromethane/methanol (4:1) and purified by silica gel chromatography. The 3-O-protecting group was removed by reaction with 48% HBr at 64 to 65° C. for 6.5 hours and the mixture was concentrated to an oil by rotary evaporation at 22 to 25° C. Purification of the crude product was carried out by ion exchange on a bromide column and a solid was isolated from selected pooled fractions. Serial recrystallization of the solid from methanol yielded a white product (64% yield). Product analysis showed an isomer distribution of approximately 97% R-isomer and 3% S-isomer. Additional recrystallizations and/or chromatography (up to 10 times) were required to eliminate the S-isomer. Hence, a need remains for further improvement.